Arginine methylation of HSP70 regulates retinoid acid-mediated RARβ2 gene activation
Arginine methylation of HSP70 regulates retinoid acid-mediated RARβ2 gene activation
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HSP70 的精氨酸甲基化调节视黄酸介导的 RARbeta2 基因激活。
DOI：
10.1073/pnas.1509658112
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发表时间：
2015-06-30
影响因子：
11.1
通讯作者：
Liu, Wen
中科院分区：
文献类型：
--
作者：
Gao, Wei-wei;Xiao, Rong-quan;Liu, Wen
尽管“组蛋白”甲基转移酶和去甲基酶已经很好地被用来调节转录程序和使用非组蛋白作为底物，但它们在核中调节热休克蛋白中的可能作用还没有被研究。在这里，我们报道了HSP70(70 kDa的热休克蛋白)蛋白中高度保守的精氨酸残基R469，这是一个进化上保守的ATP依赖的分子伴侣蛋白家族，在体外和培养细胞中，至少部分地被共激活相关的精氨酸甲基转移酶1/蛋白精氨酸甲基转移酶4(CARM1/PRMT4)单甲基化(ME1)，并被含juonji结构域的6(JMJD6)去甲基化。功能研究表明，HSP70通过与染色质结合，直接调节视黄酸受体β2(RARβ2)基因转录，其中R469me1在这一过程中起重要作用。热休克蛋白70的S功能在基因转录调控中的作用似乎与其蛋白伴侣活性不同。R469me1介导了HSP70和TFIIH之间的相互作用，参与了RNA聚合酶II的磷酸化，从而启动了转录。我们的发现扩大了PRMT4和JMJD6靶向的非组蛋白底物的谱系，并揭示了HSP70蛋白除了在蛋白质折叠和质量控制中的经典作用外，还在染色质水平上的基因转录中的新功能。
Although "histone" methyltransferases and demethylases are well established to regulate transcriptional programs and to use nonhistone proteins as substrates, their possible roles in regulation of heat-shock proteins in the nucleus have not been investigated. Here, we report that a highly conserved arginine residue, R469, in HSP70 (heat-shock protein of 70 kDa) proteins, an evolutionarily conserved protein family of ATP-dependent molecular chaperone, was monomethylated (me1), at least partially, by coactivator-associated arginine methyltransferase 1/protein arginine methyltransferase 4 (CARM1/PRMT4) and demethylated by jumonji-domain-containing 6 (JMJD6), both in vitro and in cultured cells. Functional studies revealed that HSP70 could directly regulate retinoid acid (RA)-induced retinoid acid receptor beta 2 (RAR beta 2) gene transcription through its binding to chromatin, with R469me1 being essential in this process. HSP70's function in gene transcriptional regulation appears to be distinct from its protein chaperon activity. R469me1 was shown to mediate the interaction between HSP70 and TFIIH, which involves in RNA polymerase II phosphorylation and thus transcriptional initiation. Our findings expand the repertoire of nonhistone substrates targeted by PRMT4 and JMJD6, and reveal a new function of HSP70 proteins in gene transcription at the chromatin level aside from its classic role in protein folding and quality control.